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The AP-1 transcription factor Batf controls TH17 differentiation


Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains1. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity3,4,5,6,7,8. Here we show that Batf is required for the differentiation of IL17-producing T helper (TH17) cells9. TH17 cells comprise a CD4+ T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity10,11,12,13. Batf-/- mice have normal TH1 and TH2 differentiation, but show a defect in TH17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf-/- T cells fail to induce known factors required for TH17 differentiation, such as RORγt11 (encoded by Rorc) and the cytokine IL21 (refs 14–17). Neither the addition of IL21 nor the overexpression of RORγt fully restores IL17 production in Batf-/- T cells. The Il17 promoter is BATF-responsive, and after TH17 differentiation, BATF binds conserved intergenic elements in the Il17a–Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in TH17 differentiation.

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Figure 1: Loss of IL17 production in Batf -/- T cells.
Figure 2: Batf -/- mice are resistant to EAE.
Figure 3: BATF controls several T H 17-associated genes.
Figure 4: BATF directly regulates IL17 expression.

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Primary accessions


Data deposits

Microarray data are available at Array Express ( under the accession numbers E-MEXP-1518, E-MEXP-2152 and E-MEXP-2153.


  1. 1

    Wagner, E. F. & Eferl, R. Fos/AP-1 proteins in bone and the immune system. Immunol. Rev. 208, 126–140 (2005)

    CAS  Article  Google Scholar 

  2. 2

    Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Iacobelli, M., Wachsman, W. & McGuire, K. L. Repression of IL-2 promoter activity by the novel basic leucine zipper p21SNFT protein. J. Immunol. 165, 860–868 (2000)

    CAS  Article  Google Scholar 

  4. 4

    Blank, V. Small Maf proteins in mammalian gene control: mere dimerization partners or dynamic transcriptional regulators? J. Mol. Biol. 376, 913–925 (2008)

    CAS  Article  Google Scholar 

  5. 5

    Williams, K. L. et al. Characterization of murine BATF: a negative regulator of activator protein-1 activity in the thymus. Eur. J. Immunol. 31, 1620–1627 (2001)

    CAS  Article  Google Scholar 

  6. 6

    Echlin, D. R., Tae, H. J., Mitin, N. & Taparowsky, E. J. B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks cellular transformation by Ras and Fos. Oncogene 19, 1752–1763 (2000)

    CAS  Article  Google Scholar 

  7. 7

    Dorsey, M. J. et al. B-ATF: a novel human bZIP protein that associates with members of the AP-1 transcription factor family. Oncogene 11, 2255–2265 (1995)

    CAS  PubMed  Google Scholar 

  8. 8

    Thornton, T. M., Zullo, A. J., Williams, K. L. & Taparowsky, E. J. Direct manipulation of activator protein-1 controls thymocyte proliferation in vitro. Eur. J. Immunol. 36, 160–169 (2006)

    CAS  Article  Google Scholar 

  9. 9

    Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunol. 6, 1123–1132 (2005)

    CAS  Article  Google Scholar 

  10. 10

    Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005)

    CAS  Article  Google Scholar 

  11. 11

    Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006)

    CAS  Article  Google Scholar 

  12. 12

    Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Brustle, A. et al. The development of inflammatory TH17 cells requires interferon-regulatory factor 4. Nature Immunol. 8, 958–966 (2007)

    Article  Google Scholar 

  14. 14

    Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Wei, L., Laurence, A., Elias, K. M. & O’Shea, J. J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J. Biol. Chem. 282, 34605–34610 (2007)

    CAS  Article  Google Scholar 

  17. 17

    Zhou, L. et al. IL-6 programs TH17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967–974 (2007)

    CAS  Article  Google Scholar 

  18. 18

    Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006)

    CAS  Article  Google Scholar 

  19. 19

    Bower, K. E., Fritz, J. M. & McGuire, K. L. Transcriptional repression of MMP-1 by p21SNFT and reduced in vitro invasiveness of hepatocarcinoma cells. Oncogene 23, 8805–8814 (2004)

    CAS  Article  Google Scholar 

  20. 20

    Hess, J., Angel, P. & Schorpp-Kistner, M. AP-1 subunits: quarrel and harmony among siblings. J. Cell Sci. 117, 5965–5973 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Williams, K. L. et al. BATF transgenic mice reveal a role for activator protein-1 in NKT cell development. J. Immunol. 170, 2417–2426 (2003)

    CAS  Article  Google Scholar 

  22. 22

    Zhumabekov, T., Corbella, P., Tolaini, M. & Kioussis, D. Improved version of a human CD2 minigene based vector for T cell-specific expression in transgenic mice. J. Immunol. Methods 185, 133–140 (1995)

    CAS  Article  Google Scholar 

  23. 23

    Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009)

    CAS  PubMed  Google Scholar 

  24. 24

    Yang, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008)

    CAS  Article  Google Scholar 

  25. 25

    Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Ichiyama, K. et al. Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. J. Biol. Chem. 283, 17003–17008 (2008)

    CAS  Article  Google Scholar 

  28. 28

    Zhang, F., Meng, G. & Strober, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nature Immunol. 9, 1297–1306 (2008)

    CAS  Article  Google Scholar 

  29. 29

    Zhu, H. et al. Unexpected characteristics of the IFN-γ reporters in nontransformed T cells. J. Immunol. 167, 855–865 (2001)

    CAS  Article  Google Scholar 

  30. 30

    Hertz, G. Z. & Stormo, G. D. Identifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics 15, 563–577 (1999)

    CAS  Article  Google Scholar 

  31. 31

    Gorman, J. R. et al. The Igκ enhancer influences the ratio of Igκ versus Igλ B lymphocytes. Immunity 5, 241–252 (1996)

    CAS  Article  Google Scholar 

  32. 32

    Ranganath, S. et al. GATA-3-dependent enhancer activity in IL-4 gene regulation. J. Immunol. 161, 3822–3826 (1998)

    CAS  PubMed  Google Scholar 

  33. 33

    Zhumabekov, T., Corbella, P., Tolaini, M. & Kioussis, D. Improved version of a human CD2 minigene based vector for T cell-specific expression in transgenic mice. J. Immunol. Methods 185, 133–140 (1995)

    CAS  Article  Google Scholar 

  34. 34

    Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000)

    ADS  CAS  Article  Google Scholar 

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We thank R. Lallone for anti-BATF antibody preparation, and B. Sleckman for Cre-expressing adenovirus. This work was supported by the Howard Hughes Medical Institute (K.M.M.), and grants from the National Institutes of Health HG00249 and training grant GM07200 (G.D.S.), AI035783 (C.T.W.), AR049293 (R.D.H.), and from Daiichi-Sankyo Co. Ltd (C.T.W.).

Author Contributions B.U.S. generated Batf-/- mice, designed and analysed the experiments, interpreted results and wrote the manuscript. K.H. constructed the targeting vector and probes, transgenic vector, and recombinant BATF. W.I. helped with retroviral expression experiments. W.-L.L. helped with reverse-strand reporter analysis. W.A.-E.S. helped with mouse generation. B.S. helped with EMSA analysis. G.S. and G.D.S. performed bioinformatics analysis for the BATF binding elements. J.S. and J.H.R. helped with EAE experiments. R.M., R.D.H. and C.T.W. performed ChIP experiments. T.L.M. and S.C. performed confocal microscopy for BATF. K.M.M. directed the study and wrote the manuscript.

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Corresponding author

Correspondence to Kenneth M. Murphy.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-14 with Legends, Supplementary Tables 1, 5-6, Supplementary Methods and Supplementary References. (PDF 1930 kb)

Supplementary Table 2

This file contains microarray data in Excel format accompanying Figure 3c. (XLS 27 kb)

Supplementary Table 3

This file contains microarray data in Excel format accompanying Supplementary Figure 9a. (XLS 1 kb)

Supplementary Table 4

This file contains Gene ChIP data in Excel format accompanying Supplementary Figure 9b. (XLS 1 kb)

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Schraml, B., Hildner, K., Ise, W. et al. The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460, 405–409 (2009).

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